Peptidase inhibitor 16 is a membrane-tethered regulator of chemerin processing in the myocardium

Abstract

A key response of the myocardium to stress is the secretion of factors with paracrine or endocrine function. Intriguing in this respect is peptidase inhibitor 16 (PI16), a member of the CAP family of proteins which we found to be highly upregulated in cardiac disease. Up to this point, the mechanism of action and physiological function of PI16 remained elusive. Here, we show that PI16 is predominantly expressed by cardiac fibroblasts, which expose PI16 to the interstitium via a glycophosphatidylinositol (-GPI) membrane anchor. Based on a reported genetic association of PI16 and plasma levels of the chemokine chemerin, we investigated whether PI16 regulates post-translational processing of its precursor pro-chemerin. PI16-deficient mice were engineered and found to generate higher levels of processed chemerin than wildtype mice. Purified recombinant PI16 efficiently inhibited cathepsin K, a chemerin-activating protease, in vitro. Moreover, we show that conditioned medium from PI16-overexpressing cells impaired the activation of pro-chemerin. Together, our data indicate that PI16 suppresses chemerin activation in the myocardium and suggest that this circuit may be part of the cardiac stress response.

PI16 is a non-neuronal regulator of neuropathic pain

“…chemerin and MMP2 9,11 . PI16 has been described to inhibit the proteolytic activation of the chemoattractant chemerin 9,11 . However, we did not detect any difference in the expression of precursor- and activated-chemerin in the lumbar DRGs between WT and Pi16−/− post SNI (Figure 7C).…”

“…Previous studies have identified two possible targets of PI16 that could contribute to changes in leukocyte migration/infiltration, i.e. chemerin and MMP2 9,11 . PI16 has been described to inhibit the proteolytic activation of the chemoattractant chemerin 9,11 .…”

“…Mouse PI16 was first identified from a cardiac cDNA library and shown to be a glycosylated protein with expression in intercellular spaces, secretory vesicles, and a predicted role in the extracellular matrix 8 . Another study showed a strong upregulation of PI16 in a mouse model of heart failure and indicated a potential paracrine role of PI16 in cardiac hypertrophy 8,9 However, genetic deletion of Pi16 conferred no phenotype at the level of cardiac structure or function indicating functional redundancy in the heart 9 . In our study, however, we demonstrate that PI16 is an important regulator of neuropathic pain.…”

“…Our finding that PI16,aa protein that is not detectable in neurons and glia plays a key role in neuropathic pain add to the growing awareness that multiple non-neuronal cells types are actively involved in maintenance and resolution of chronic pain and may represent important targets for the treatment of chronic pain. In this respect we see PI16 as an interesting potentially druggable target for chronic pain considering its expression is restricted to very few organs (heart, bladder, mammary, fat) (https://tabula-muris.ds.czbiohub.org/)and, crucially, genetic deletion of Pi16 does not affect the cardiac function 9 , an organ in which PI16 is expressed at a high level.…”

“…Very little is known about the tissue distribution and function of PI16. What is known is that PI16 is expressed in cardiac fibroblasts, but PI16-deficient mice do not have a cardiac phenotype 8,9 There is evidence that Pi16 regulates processing of the chemokine chemerin 9 , cutaneous cathepsin K 10 , and of the matrix metalloprotease MMP2 in endothelial cells 11 . There is no previous evidence for a role of PI16 in pain signaling.…”